title: Double suicide gene therapy using human neural stem cells against glioblastoma: double safety measures.
abstract: With recent advancements in stem cell-based gene therapy, concerns about safety have grown. Stem cell-based gene therapies may pose the risk of immunological problems and oncogenesis. We investigated the feasibility of treating glioblastomas with neural stem cells [(NSCs), HB1.F3 cells] expressing double prodrug enzymes [cytosine deaminase (CD) and tyrosine kinase (TK)] to eliminate the NSCs following treatment for safety purposes. First, the in vitro and in vivo therapeutic efficacies of NSCs engineered with double prodrug enzymes (HB1.F3-CD.TK cells) were compared to cells expressing a single prodrug enzyme (HB1.F3-CD). Second, the degree of safety achieved by NSC elimination was compared with an in vitro viability assay of the NSCs after treatment with the double prodrugs. We further compared the differences in in vivo proliferation of control, single prodrug enzyme and double prodrug enzyme expressing NSCs. HB1.F3-CD.TK cells showed a better or comparable treatment outcome than HB1.F3-CD cells in vitro and in vivo. For safety, HB1.F3-CD.TK cells showed the least viability in vitro after treatment with prodrugs compared to HB1.F3 and HB1.F3-CD cells. Additionally, the in vivo proliferation among the injected NSCs found in the tumor was the smallest for HB1.F3-CD.TK cells. Double-prodrug enzyme-directed gene therapy shows good therapeutic efficacy as well as efficient eradication of the NSCs to ensure safety for clinical applications of stem cell-based gene therapies.
authors.affiliation: Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.
authors.forename: Ji Yeoun
authors.initials: JY
authors.lastname: Lee
authors.forename: Do-Hun
authors.initials: DH
authors.lastname: Lee
authors.forename: Hyung A
authors.initials: HA
authors.lastname: Kim
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Choi
authors.forename: Hong Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Phi
authors.forename: Kyu-Chang
authors.initials: KC
authors.lastname: Wang
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival; D004195:Disease Models, Animal; D041722:Genes, Transgenic, Suicide / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation
chemical_list: D019394:Ki-67 Antigen